Sildenafil

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Abstract
Erectile dysfunction is the inability of a male to achieve and maintain an erect penis as a part of overall male sexual function. The most common organic causes of erectile dysfunction are vascular, neurological and pharmacological. The incidence of erectile dysfunction generally increases with advancing age. The pharmacological effects of agents such as sildenafil can be measured objectively, but because of the personal and interpersonal nature of erectile function, clinical assessment of the drug must rely on subjective reports from patients. Objective pharmacodynamic measurement of the response of erectile function to sildenafil in humans is primarily performed by determining penile rigidity in response to visual sexual stimulation. Clinical assessments are made using a detailed sexual questionnaire surveying patients on general issues such as whether they thought their erections had improved, supplemented by diary data and partner surveys. Sildenafil promotes erections in response to sexual stimulation by inducing smooth muscle relaxation in the corpus cavernosum through selective inhibition of phosphodiesterase type 5 (PDE5). By reducing the inactivation of cyclic guanosine monophosphate (cGMP) rather than promoting its production, sildenafil promotes penile erection only in response to sexual stimulation, but has no effects in the absence of sexual stimulation. Indeed, the effects of sildenafil on cGMP were enhanced by sodium nitroprusside in rabbit corpus cavernosum in vitro, indicating that sildenafil augments nitric oxide-mediated activity in this tissue. The activity of sildenafil is highly selective, being 80- to >8500-fold greater against human PDE5 than against several other human PDEs and 7.7- to 16.6-fold greater against human PDE5 than PDE6. In well controlled studies in patients with erectile dysfunction of a variety of causes, single doses of sildenafil enabled more men to achieve an erection than placebo, and erections were maintained for longer with sildenafil than placebo. More patients achieved >60% rigidity of the base of the penis, and this rigidity lasted for longer, with sildenafil than placebo. Single doses of sildenafil appear to produce dose-related rigidity at the base and tip of the penis in response to visual sexual stimulation. Daily sildenafil improved erections in more patients than placebo and was associated with an increased rate of erections (6.1 vs 1.3 erections in 7 days, p = 0.005). Blood pressure was transiently reduced by sildenafil 100mg, and larger blood pressure reductions may occur when sildenafil is given with nitrates; the ECG, however, did not change. Dose-related effects of sildenafil on retinal PDE6 may cause the impairment of colour (blue/green) discrimination seen with sildenafil, but the drug had no major effects on vision in healthy volunteers. Sildenafil alone or with aspirin has no effects on bleeding time, but sodium nitroprusside-induced inhibition of platelet aggregation was increased in vitro by sildenafil. Oral sildenafil is rapidly absorbed, with peak plasma concentrations (Cmax) occurring within 1 hour. Absolute bioavailability was 41%. Food slows absorption but does not affect the area under the plasma sildenafil concentration-time curve (AUC). AUC and Cmax were dose-proportional over single sildenafil doses from 1.25 to 200mg. The steady-state volume of distribution was 105L, indicating wide distribution. Plasma protein binding was ≈96%. The elimination half-life was 3 to 5 hours. ≈80% of a dose was found in the faeces and ≈13% in the urine as metabolites; N-demethylation by CYP3A4 is the major route of metabolism. Clearance of sildenafil is reduced in healthy elderly patients, patients with renal insufficiency (creatinine clearance vs 1.5 attempts with placebo, p < 0.001) and 69% of attempts at sexual intercourse were successful in sildenafil recipients (vs 22% with placebo, p < 0.001). A 200mg sildenafil dose did not provide additional efficacy over that seen with a 100mg dose, but tended to produce more adverse events. Early trials of sildenafil in patients with erectile dysfunction of no known organic cause found 3-fold more frequent erections and more patients reporting improvements in erections with sildenafil (65 to 93%) than placebo (20 and 27%). Dose-response effects of sildenafil 10, 25 and 50mg were reported on hardness, frequency and duration of erections and frequency of sexual intercourse in 1 trial, but the drug did not alter the number of attempts at intercourse. After a single dose of sildenafil 50mg, 86% of patients subsequently randomised to placebo reported their erections were ‘worse’ during placebo than they had been during sildenafil treatment; patients also reported more frequent erections in the sildenafil than placebo groups. 87% of sildenafil recipients had doses titrated to 50 or 100mg. Significant improvements in ability to achieve and maintain erections were seen in diabetic patients receiving sildenafil 25 to 100mg compared with placebo in a 12-week dose-titration study in 268 patients. At the end of the study, 93% of sildenafil recipients required 100mg doses for efficacy. Data from subgroup analysis of 692 patients with diabetes in both dose-titration and fixed-dose therapeutic trials lasting 6 to 26 weeks showed similar improvements in erections and the ability to achieve and maintain erections. Whether or not patients had residual erectile function, sildenafil was significantly more effective than placebo for erectile dysfunction caused by spinal cord injuries, with improvements in erections seen in 64% of sildenafil recipients with no residual erectile function and 75 and 78% of those with erectile function. Subgroup analysis from the major clinical trials suggests that men with severe erectile dysfunction respond better to sildenafil than to placebo and that sildenafil is similarly effective in broader patient populations and in patients undergoing antihypertensive therapy, aged ≥65 years or those experiencing depression. Trials in small numbers of patients with heart transplants or receiving maintenance haemodialysis for end-stage renal disease suggest that sildenafil can be effective, although effects of the drug were prolonged in the dialysis patients. The efficacy of sildenafil appears to be maintained after long term treatment. There are reports of significant positive effects of sildenafil on patients’ quality of life and on female partners’ satisfaction and perceptions of treatment. Significant improvements (p < 0.05) were seen on 7 of 11 quality of life end-points after 12 weeks ’ treatment with sildenafil compared with placebo in a pooled population of 940 patients with broad spectrum erectile dysfunction. In a dose-titration study, partner ratings significantly favouring sildenafil were reported. Female partners of patients with spinal cord injury reported greater personal satisfaction with sexual intercourse and improvements in their partners’ erections after the 178 patients received sildenafil than after placebo. Sildenafil was very well tolerated in clinical trials, with the most commonly reported adverse events being headache, flushing, dyspepsia and nasal congestion. Adverse events were generally transient and mild to moderate and occurred in similar proportions of patients receiving sildenafil and placebo. The incidence of commonly reported adverse events or discontinuations from therapy was dose-related. Vision changes were mild and transient, and included a colour tinge to vision, increased sensitivity to light or blurred vision. In clinical trials, the tolerability of sildenafil in patients receiving antihypertensive medications was similar to that seen in general study populations. There are isolated reports of painful, prolonged erections. In long term studies, sildenafil was well tolerated and headache (10%), flushing (9%), dyspepsia (6%) and respiratory tract infection (6%) were the most common adverse events. Abnormal vision occurred in 2% of patients and no long term vision problems were noted. Good tolerability and low withdrawal rates were seen during 2 years’ treatment. In clinical trials, no serious adverse events were judged to be related to sildenafil therapy. The incidence of serious cardiovascular events in patients receiving sildenafil was similar to that in patients receiving placebo. After >6 million sildenafil prescriptions were dispensed, most of the 130 deaths associated with sildenafil appear to have occurred in patients with known risk factors or contraindications to the use of the drug (e.g. known or suspected myocardial infarction, cardiac arrest, cardiac symptoms, coronary artery disease, concomitant nitrate use). Symptoms leading to death occurred most often within 4 to 5 hours after administration. 70% of patients had risk factors for cardiovascular disease. The interaction between sildenafil and organic nitrates contraindicates the concomitant use of these drugs. The potential exists for interactions between sildenafil and inhibitors or inducers of CYP3A4 and CYP2C9; however, only CYP3A4-related interactions have been documented (e.g. with erythromycin, ritonavir, saquinavir, ketoconazole, itraconazole or cimetidine). Rifampicin (rifampin), a CYP3A4 inducer, is expected to decrease sildenafil plasma concentrations. Sildenafil does not appear to interact with magnesium hydroxide/aluminium hydroxide antacids, thiazide diuretics, ACE inhibitors, calcium antagonists, alcohol, amlodipine, the CYP2C9 inhibitors tolbutamide and warfarin or CYP2D6 inhibitors such as selective serotonin reuptake inhibitors or tricyclic antidepressants. Sildenafil is indicated as an oral therapy for male patients with erectile dysfunction. In the US, sildenafil is contraindicated in patients taking organic nitrates or nitric oxide donors and in those for whom sexual activity carries a major cardiovascular risk; it should be used with caution in patients with recent heart attack, stroke, life-threatening arrhythmia, significant hypo- or hypertension, unstable angina, heart disease that could be affected by reductions in blood pressure, or retinitis pigmentosa. In Europe, contraindications to the use of sildenafil include the use of nitrates or nitric oxide donors and patients in whom sexual activity is not advised (e.g. patients with severe cardiac illness such as unstable angina or severe heart failure), those with hypotension, severe hepatic impairment, retinitis pigmentosa, or a recent history of stroke or myocardial infarction. The usual dosage of sildenafil is a single 50mg dose taken when needed ≈1 hour before sexual activity, but the drug may be taken from 0.5 to 4 hours before sexual activity. No more than 1 dose should be taken in any given day. Depending on effectiveness and tolerability, single doses may be increased to a maximum of 100mg or reduced to 25mg. A lower (25mg) initial dose may be considered in patients aged >65 years, or those with hepatic impairment or moderate to severe renal impairment (creatinine clearance <1.8 L/h or <30 ml/min), or those receiving concomitant CYP3A4 inhibitors (e.g. ritonavir, saquinavir, erythromycin, ketoconazole, itraconazole).